Correspondence
Vitamin E and the Risk of Coronary Disease
N Engl J Med 1993; 329:1424-1426November 4, 1993
- Article
To the Editor:
The two studies suggesting a substantial reduction in the risk of coronary heart disease associated with the use of vitamin E supplements (May 20 issue)1,2 provide further compelling evidence about the importance of oxidation in the process of atherogenesis. We take issue, however, with the conclusion that it is premature to recommend vitamin E supplementation for the prevention of coronary heart disease3.
Until recently, physicians have generally maintained a healthy skepticism about vitamin supplementation, viewing it as unnecessary but probably harmless (when given in reasonable dose ranges). Vitamin E appears to provide substantial protection against coronary heart disease at minimal cost. Numerous studies have used vitamin E in the dose range of 200 to 800 IU per day, with virtually no reported toxicity4. The arguments for withholding this treatment from patients who have coronary heart disease or are at high risk for it while investigation continues are unconvincing, especially in the context of current practices in clinical cardiology. For example, the use of coronary angioplasty (which is expensive and is associated with considerable morbidity as compared with vitamin E) has grown exponentially since its introduction in 1977. Yet randomized trials documenting the effectiveness of elective coronary angioplasty in prolonging life or reducing cardiac events are still not available. At the very least, physicians should sanction the use of vitamin E in patients who have coronary heart disease or are at high risk, especially the growing number of patients who ask permission to use it. A substantial number of physicians in the United States are sufficiently convinced of the potential benefits and nontoxic nature of vitamin E to supplement their own diets with it. If vitamin E is good enough for physicians, should it not be good enough for our patients?
4 ReferencesJames H. O'Keefe, Jr., M.D.
Mid America Heart Institute, Kansas City, MO 64111Carl J. Lavie, M.D.
Ochsner Heart and Vascular Institute, New Orleans, LA 701211
Rimm EB ,Stampfer MJ ,Ascherio A ,Giovannucci E ,Colditz GA ,Willett WC . Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-1456
Full Text | Web of Science | Medline2
Stampfer MJ ,Hennekens CH ,Manson JE ,Colditz GA ,Rosner B ,Willett WC . Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-1449
Full Text | Web of Science | Medline3
Steinberg D . Antioxidant vitamins and coronary heart disease. N Engl J Med 1993;328:1487-1489
Full Text | Web of Science | Medline4
Bendich A ,Machlin LJ . Safety of oral intake of vitamin E. Am J Clin Nutr 1988;48:612-619
Web of Science | Medline
To the Editor:
Reduction in the oxidation of low-density lipoproteins by the antioxidant action of vitamin E is a possible explanation of the findings of Stampfer et al. and Rimm et al. However, the platelet is the principal protagonist in the development of the cardiovascular complications (e.g., myocardial infarction and ischemic stroke) that constituted the end points of the study. My colleagues and I have shown that dietary vitamin E supplementation is very effective in inhibiting platelet adhesion ex vivo1. This effect of vitamin E is probably mediated by an action not directly related to its antioxidant activity2. In distinct contrast, vitamin E was a poor inhibitor of platelet aggregation (release) when tested ex vivo,3 even though it showed good inhibition in vitro4. This may be due to the inherently very high antioxidant capacity of plasma, which obscures the effect of the vitamin E supplement. Reduced platelet adhesiveness may have played an important part in preventing cardiovascular complications in the two studies.
4 ReferencesManfred Steiner, M.D., Ph.D.
Memorial Hospital of Rhode Island, Pawtucket, RI 028601
Jandak J ,Steiner M ,Richardson PD . alpha-Tocopherol, an effective inhibitor of platelet adhesion. Blood 1989;73:141-149
Web of Science | Medline2
Steiner M . Vitamin E: more than an antioxidant. Clin Cardiol 1993;16:I16-I18
CrossRef | Web of Science | Medline3
Steiner M . Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost 1983;49:73-77
Web of Science | Medline4
Steiner M ,Anastasi J . Vitamin E: an inhibitor of the platelet release reaction. J Clin Invest 1976;57:732-737
CrossRef | Web of Science | Medline
To the Editor:
In the study by Stampfer et al., the data on vitamin E supplements were updated every two years, and women who had reached an end point were excluded at that time, but dietary intake of vitamin E and all the other potential confounding variables were measured only at base line, putting the information that was not updated at a distinct disadvantage in the comparison. A fairer test for confounding would result from a multivariate analysis using base-line data for all variables and predicting all incident events that occurred during follow-up.
The companion paper by Rimm et al. is persuasive because the observed relative risk of coronary events was exactly the same in men as in women. The two relative risks were calculated with very different thresholds, however: a median of 208 IU of vitamin E per day for the women in the highest quintile group and a median of 419 IU per day for the men. No analyses of the use of vitamin E supplements either as a continuous variable or in different dosages are presented. This makes it difficult to determine whether this relation involves a threshold or is graded. This information would be very useful.
Lynda H. Powell, Ph.D.
Henry R. Black, M.D.
Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612To the Editor:
There is a growing literature on the role of a major pro-oxidant, iron, in ischemic heart disease1,2. Abundant evidence implicates iron as a pro-oxidant that can promote tissue injury1,2. Excess iron can be removed from the body by safe, inexpensive methods. The development of heart disease may depend not simply on concentrations of antioxidants, but also on the balance between antioxidants and pro-oxidants.
As Steinberg points out, there was no difference in the risk of disease over the range of vitamin E intakes from natural foodstuffs. Only high pharmacologic levels of vitamin E consumption were associated with decreased risk. Perhaps pro-oxidant iron levels were so high in the subjects that an abnormally high consumption of vitamin E was needed for protection. A much lower intake of vitamin E may protect those with lower serum ferritin levels. High doses of vitamin E are not needed to provide the remarkable protection against heart disease enjoyed by menstruating women. A lower physiologic level of vitamin E may protect menstruating women because they have low levels of excess (stored) iron.
2 ReferencesJerome L. Sullivan, M.D., Ph.D.
Veterans Affairs Medical Center, Charleston, SC 29401-57991
Sullivan JL . Stored iron and ischemic heart disease: empirical support for a new paradigm. Circulation 1992;86:1036-1037
Web of Science | Medline2
Salonen JT ,Nyyssonen K ,Korpela H ,Tuomilehto J ,Seppanen R ,Salonen R . High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803-811
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Drs. O'Keefe and Lavie that physicians may advise patients about the potential cardiovascular benefits of vitamin E supplementation. However, we believe that without data from clinical trials, the evidence is insufficient for use in public policy. It is critical that if vitamin E is used, it not serve as an excuse to relax efforts to decrease the better-established risk factors for coronary heart disease. In addition, there is little evidence about the effects of vitamin E supplementation in secondary prevention.
In response to Dr. Steiner, our group1 and others have found that in placebo-controlled, double-blind clinical trials, vitamin E supplementation does not reduce platelet aggregation. Moreover, in both our studies2,3 we found that those who used supplements for less than two years had no appreciable reduction in risk, a finding more consistent with an effect on atherosclerosis. An effect on platelets cannot be fully ruled out, however.
As stated in the Methods section of our paper on women,2 only dietary vitamin E intake was not updated with data from each of the biennial questionnaires. Data on all confounding variables and vitamin supplementation were updated. When we repeated our analyses and examined the cumulative incidence of coronary heart disease over the eight-year follow-up period using only base-line data, our results were not appreciably different.
As Powell and Black point out, the median vitamin E intake in the highest quintile groups for total intake was higher in men, reflecting more use of high-dose supplementation. However, we found that supplementation above 100 IU per day did not further decrease the risk of coronary heart disease among women2 or among men3.
The association between iron and the risk of coronary disease is controversial. The widely publicized Finnish study,4 based on 51 cases, reported an increased risk, but preliminary data from larger studies have not replicated these findings5. We do not have base-line serum ferritin levels of women or men from these populations. Although total iron intake was higher among participants taking vitamin E supplements, intake of heme iron, which is more readily absorbed than bound iron, was marginally lower in participants reporting use of vitamin E supplementation. Furthermore, control for heme iron or total iron in our multivariate models did not appreciably change our results.
The notion that low iron stores explain the low risk among premenopausal women is refuted by the finding that among premenopausal women who undergo oophorectomy, the twofold excess risk of heart disease is completely eliminated by estrogen therapy6.
6 ReferencesMeir J. Stampfer, M.D.
Eric B. Rimm, Sc.D.
Walter C. Willett, M.D.
Harvard School of Public Health, Boston, MA 021151
Stampfer MJ ,Jakubowski JA ,Faigel D ,Vaillancourt R ,Deykin D . Vitamin E supplementation effect on human platelet function, arachidonic acid metabolism, and plasma prostacyclin levels. Am J Clin Nutr 1988;47:700-706
Web of Science | Medline2
Stampfer MJ ,Hennekens CH ,Manson JE ,Colditz GA ,Rosner B ,Willett WC . Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-1449
Full Text | Web of Science | Medline3
Rimm EB ,Stampfer MJ ,Ascherio A ,Giovannucci E ,Colditz GA ,Willett WC . Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-1456
Full Text | Web of Science | Medline4
Salonen JT ,Nyyssonen K ,Korpela H ,Tuomilehto J ,Seppanen R ,Salonen R . High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803-811
Web of Science | Medline5
Stampfer MJ ,Grodstein F ,Rosenberg I ,Willett WC ,Hennekens CH . A prospective study of plasma ferritin and risk of myocardial infarction in US physicians. Circulation 1993;87:Suppl XX:10-10 abstract.6
Stampfer MJ ,Colditz GA ,Willett WC , et al. Postmenopausal estrogen therapy and cardiovascular disease -- ten-year follow-up from the Nurses' Health Study. N Engl J Med 1991;325:756-762
Full Text | Web of Science | Medline
Author/Editor Response
Drs. O'Keefe and Lavie take issue with my position that it is premature to recommend vitamin E supplementation for the prevention of coronary heart disease1. They say, “Vitamin E appears to provide substantial protection against coronary heart disease.” “Appears” is the operative word. Yes, there is impressive experimental evidence for the hypothesis that oxidation of low-density lipoprotein plays a major part in atherosclerosis and that such oxidation occurs in humans2,3. There is also epidemiologic evidence correlating vitamin E intake with an increased risk of coronary heart disease, including two recent papers in the Journal4,5. However, not a single clinical intervention trial demonstrating efficacy has been published in detail. “Appearing” to provide protection just will not do. The analogy with the current widespread use of prophylactic angioplasty is more an argument for appropriate evaluation of that intervention than a justification for a green light on other incompletely tested interventions. Moreover, the analogy is not exact: the benefits of angioplasty have at least been demonstrated in patients with symptomatic coronary heart disease, whereas there is no evidence of clinical benefit from vitamin E supplementation at any stage of this disease.
Drs. O'Keefe and Lavie make the “It can't hurt” argument. I agree that vitamin E is unlikely to be toxic, which would justify lowering the required level of proof of efficacy. But it certainly does not totally remove the need for such proof. Moreover, once the use of vitamin E is endorsed, even if only in high-risk patients, most patients will conclude that it is beneficial and will probably neglect risk factors that are well established but that take more than pill-popping to change (e.g., smoking and intake of saturated fat).
Finally, Drs. O'Keefe and Lavie say that many physicians are convinced that vitamin E works, sufficiently so to be taking it themselves, thus implying that this fact alone justifies recommending its use. I cannot agree. We must insist on an objective demonstration of efficacy. Recall that at one time most physicians were convinced of the value of prophylactic tonsillectomy.
I find myself in the somewhat anomalous position of arguing against clinical intervention and medical advice based on a hypothesis that my colleagues and I played a major part in developing2,3. Do I believe that vitamin E supplementation will prove efficacious? I certainly hope so. However, that makes me no less demanding of clinical proof of efficacy than I would be in the case of any other proposed intervention. At the same time, I recognize that proof is not an all-or-nothing matter; there are levels of proof. Even results of clinical trials have P values attached to them. Practitioners (and patients, too, since prescriptions are not required) will decide for themselves what to do about vitamin E. They should be clear, however, that at this time no one can flatly state, “This medicine will help you.” And there is no rush. Clinical intervention trials are already in progress, and we should have a definitive answer in a few years.
5 ReferencesDaniel Steinberg, M.D., Ph.D.
University of California, San Diego, San Diego, CA 92093-06821
Steinberg D . Antioxidant vitamins and coronary heart disease. N Engl J Med 1993;328:1487-1489
Full Text | Web of Science | Medline2
Steinberg D ,Parthasarathy S ,Carew TE ,Khoo JC ,Witztum JL . Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924
Full Text | Web of Science | Medline3
Steinberg D ,Witztum JL . Lipoproteins and atherogenesis: current concepts. JAMA 1990;264:3047-3052
CrossRef | Web of Science | Medline4
Stampfer MJ ,Hennekens CH ,Manson JE ,Colditz GA ,Rosner B ,Willett WC . Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-1449
Full Text | Web of Science | Medline5
Rimm EB ,Stampfer MJ ,Ascherio A ,Giovannucci E ,Colditz GA ,Willett WC . Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-1456
Full Text | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Francesco Violi, Pasquale Pignatelli. (2011) Platelet Oxidative Stress and Thrombosis. Thrombosis Research
CrossRef2
James H. O'Keefe, Robert D. Conn, Carl J. Lavie, Timothy M. Bateman. (1996) The New Paradigm for Coronary Artery Disease: Altering Risk Factors, Atherosclerotic Plaques, and Clinical Prognosis. Mayo Clinic Proceedings 71:10, 957-965
CrossRef3
James H. O'Keefe, Carl J. Lavie, Ben D. Mccallister. (1995) Insights Into the Pathogenesis and Prevention of Coronary Artery Disease. Mayo Clinic Proceedings 70:1, 69-79
CrossRef
